Baroreflex modulation based on monitored cardiovascular parameter

ABSTRACT

An aspect relates to a system for providing baroreflex stimulation. An embodiment of the system comprises a heart rate monitor to sense a heart rate and provide a signal indicative of the heart rate, and a baroreflex stimulator. The stimulator includes a pulse generator to intermittently generate a stimulation signal to provide baroreflex stimulation for a baroreflex therapy, and further includes a modulator to adjust the stimulation signal based on the signal indicative of the heart rate such that the stimulation signal provides a desired baroreflex stimulation corresponding to a desired heart rate.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 10/746,846, filed Dec. 24, 2003, entitled“Automatic Baroreflex Modulation Based on Cardiac Activity,” which isherein incorporated by reference in its entirety.

TECHNICAL FIELD

This application relates generally to implantable medical devices and,more particularly, to modulating baroreflex stimulation to provide adesired heart rate.

BACKGROUND

Implanting a chronic electrical stimulator, such as a cardiacstimulator, to deliver medical therapy(ies) is known. Examples ofcardiac stimulators include implantable cardiac rhythm management (CRM)device such as pacemakers, implantable cardiac defibrillators (ICDs),and implantable devices capable of performing pacing and defibrillatingfunctions.

CRM devices are implantable devices that provide electrical stimulationto selected chambers of the heart in order to treat disorders of cardiacrhythm. An implantable pacemaker, for example, is a CRM device thatpaces the heart with timed pacing pulses. If functioning properly, thepacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Some CRM devices synchronize pacing pulses deliveredto different areas of the heart in order to coordinate the contractions.Coordinated contractions allow the heart to pump efficiently whileproviding sufficient cardiac output.

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to heart failure. A large segment of thegeneral population, as well as a large segment of patients implantedwith pacemakers or defibrillators, suffer from hypertension. The longterm mortality as well as the quality of life can be improved for thispopulation if blood pressure and hypertension can be reduced. Manypatients who suffer from hypertension do not respond to treatment, suchas treatments related to lifestyle changes and hypertension drugs.

A pressoreceptive region or field is capable of sensing changes inpressure, such as changes in blood pressure. Pressoreceptor regions arereferred to herein as baroreceptors, which generally include any sensorsof pressure changes. For example, baroreceptors include afferent nervesand further include sensory nerve endings that are sensitive to thestretching of the wall that results from increased blood pressure fromwithin, and function as the receptor of a central reflex mechanism thattends to reduce the pressure. Baroreflex functions as a negativefeedback system, and relates to a reflex mechanism triggered bystimulation of a baroreceptor. Increased pressure stretches bloodvessels, which in turn activates baroreceptors in the vessel walls.Activation of baroreceptors naturally occurs through internal pressureand stretching of the arterial wall, causing baroreflex inhibition ofsympathetic nerve activity (SNA) and a reduction in systemic arterialpressure. An increase in baroreceptor activity induces a reduction ofSNA, which reduces blood pressure by decreasing peripheral vascularresistance.

The general concept of stimulating afferent nerve trunks leading frombaroreceptors is known. For example, direct electrical stimulation hasbeen applied to the vagal nerve and carotid sinus. Research hasindicated that electrical stimulation of the carotid sinus nerve canresult in reduction of experimental hypertension, and that directelectrical stimulation to the pressoreceptive regions of the carotidsinus itself brings about reflex reduction in experimental hypertension.

Electrical systems have been proposed to treat hypertension in patientswho do not otherwise respond to therapy involving lifestyle changes andhypertension drugs, and possibly to reduce drug dependency for otherpatients.

SUMMARY

Various aspects and embodiments of the present subject matter use amonitored cardiovascular parameter to automatically modulatebaroreceptor stimulation. The use of a monitored cardiovascularparameter allows an implantable neural stimulator to control neuralstimulation delivery to provide a targeted effect, such as on heartrate.

An aspect of the present subject matter relates to a system forproviding baroreflex stimulation. An embodiment of the system comprisesa heart rate monitor to sense a heart rate and provide a signalindicative of the heart rate, and a baroreflex stimulator. Thestimulator includes a pulse generator to intermittently generate astimulation signal to provide baroreflex stimulation for a baroreflextherapy, and further includes a modulator to adjust the stimulationsignal based on the signal indicative of the heart rate such that thestimulation signal provides a desired baroreflex stimulationcorresponding to a desired heart rate.

An embodiment of the system comprises a baroreflex stimulator, acardiovascular parameter monitor, and a comparator. The baroreflexstimulator includes a pulse generator to generate a stimulation signalto provide intermittent baroreflex stimulation for a baroreflex therapy,and further includes a modulator to adjust the stimulation signal. Thecardiovascular parameter monitor is adapted to monitor at least onecardiovascular parameter and provide a first signal indicative of thecardiovascular parameter during the baroreflex stimulation and a secondsignal indicative of the cardiovascular parameter without the baroreflexstimulation. The comparator is adapted to provide a detected change forthe cardiovascular parameter based on the first and second signals, andto provide a therapy control signal based on a desired change for thecardiovascular parameter and the detected change.

An aspect of the present subject matter relates to a method foroperating an implantable medical device. In an embodiment of the method,baroreflex stimulation is intermittently provided for a baroreflextherapy over a period of time. Values for at least one cardiovascularfeedback parameter are compared when the baroreflex stimulation isapplied and when then baroreflex stimulation is not applied to provide adetected feedback change. The detected feedback change is compared to adesired feedback change to provide a comparison result. The baroreflexstimulation is adjusted based on the comparison result to control thebaroreflex therapy over the period of time.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol.

FIGS. 2A-2C illustrate a heart.

FIG. 3 illustrates baroreceptors and afferent nerves in the area of thecarotid sinuses and aortic arch.

FIG. 4 illustrates baroreceptors in and around the pulmonary artery.

FIG. 5 illustrates baroreceptor fields in the aortic arch, theligamentum arteriosum and the trunk of the pulmonary artery.

FIG. 6 illustrates a known relationship between respiration and bloodpressure when the baroreflex is stimulated.

FIG. 7 illustrates a blood pressure response to carotid nervestimulation in a hypertensive dog during 6 months of intermittentcarotid nerve stimulation.

FIG. 8 illustrates a system including an implantable medical device(IMD) and a programmer, according to various embodiments of the presentsubject matter.

FIG. 9 illustrates an implantable medical device (IMD) such as shown inthe system of FIG. 8, according to various embodiments of the presentsubject matter.

FIGS. 10A-10C illustrate a baroreceptor stimulation lead with anintegrated pressure sensor (IPS), according to various embodiments ofthe present subject matter.

FIG. 11 illustrates an implantable medical device (IMD) such as shown inFIG. 8 having a neural stimulator (NS) component and cardiac rhythmmanagement (CRM) component, according to various embodiments of thepresent subject matter.

FIG. 12 illustrates a system including a programmer, an implantableneural stimulator (NS) device and an implantable cardiac rhythmmanagement (CRM) device, according to various embodiments of the presentsubject matter.

FIG. 13 illustrates an implantable neural stimulator (NS) device such asshown in the system of FIG. 12, according to various embodiments of thepresent subject matter.

FIG. 14 illustrates an implantable cardiac rhythm management (CRM)device such as shown in the system of FIG. 12, according to variousembodiments of the present subject matter.

FIG. 15 illustrates a programmer such as illustrated in the systems ofFIGS. 8 and 12 or other external device to communicate with theimplantable medical device(s), according to various embodiments of thepresent subject matter.

FIGS. 16A-16D illustrate a system and methods to prevent interferencebetween electrical stimulation from a neural stimulator (NS) device andsensing by a cardiac rhythm management (CRM) device, according tovarious embodiments of the present subject matter.

FIG. 17 illustrates a system to modulate baroreflex stimulation,according to various embodiments of the present subject matter.

FIGS. 18A-18C illustrate methods for modulating baroreceptor stimulationbased on a cardiac activity parameter, according to various embodimentsof the present subject matter.

FIGS. 19A-19B illustrate methods for modulating baroreceptor stimulationbased on a respiration parameter, according to various embodiments ofthe present subject matter.

FIGS. 20A-20B illustrate methods for modulating baroreceptor stimulationbased on detection of an adverse event, according to various embodimentsof the present subject matter.

FIGS. 21A-21E illustrate circadian rhythm.

FIG. 22 illustrates a method for modulating baroreceptor stimulationbased on circadian rhythm, according to various embodiments of thepresent subject matter.

FIG. 23A-B illustrate methods for modulating baroreceptor stimulationbased on a cardiac output parameter, according to various embodiments ofthe present subject matter.

FIG. 24 illustrates a method for modulating baroreceptor stimulation toreverse remodel stiffening, according to various embodiments of thepresent subject matter.

FIGS. 25A-25B illustrate a system and method to detect myocardialinfarction and perform baropacing in response to the detected myocardialinfarction, according to various embodiments of the present subjectmatter.

FIGS. 26A-26B illustrate a system and method to automatically adjust abaroreflex stimulation level to titrate a desired baroreflex therapyover an extended time based on monitored cardiovascular parameter(s),according to various embodiments of the present subject matter.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

Hypertension and Baroreflex Physiology

A brief discussion of hypertension and the physiology related tobaroreceptors is provided to assist the reader with understanding thisdisclosure. This brief discussion introduces hypertension, the autonomicnervous system, and baroreflex.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension generally relates to high blood pressure,such as a transitory or sustained elevation of systemic arterial bloodpressure to a level that is likely to induce cardiovascular damage orother adverse consequences. Hypertension has been arbitrarily defined asa systolic blood pressure above 140 mm Hg or a diastolic blood pressureabove 90 mm Hg. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure. Consequences of uncontrolled hypertension include, but are notlimited to, retinal vascular disease and stroke, left ventricularhypertrophy and failure, myocardial infarction, dissecting aneurysm, andrenovascular disease.

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes, but is not limited to, the sympathetic nervous systemand the parasympathetic nervous system. The sympathetic nervous systemis affiliated with stress and the “fight or flight response” toemergencies. Among other effects, the “fight or flight response”increases blood pressure and heart rate to increase skeletal muscleblood flow, and decreases digestion to provide the energy for “fightingor fleeing.” The parasympathetic nervous system is affiliated withrelaxation and the “rest and digest response” which, among othereffects, decreases blood pressure and heart rate, and increasesdigestion to conserve energy. The ANS maintains normal internal functionand works with the somatic nervous system.

The subject matter of this disclosure generally refers to the effectsthat the ANS has on the heart rate and blood pressure, includingvasodilation and vasoconstriction. The heart rate and force is increasedwhen the sympathetic nervous system is stimulated, and is decreased whenthe sympathetic nervous system is inhibited (the parasympathetic nervoussystem is stimulated). FIGS. 1A and 1B illustrate neural mechanisms forperipheral vascular control. FIG. 1A generally illustrates afferentnerves to vasomotor centers. An afferent nerve conveys impulses toward anerve center. A vasomotor center relates to nerves that dilate andconstrict blood vessels to control the size of the blood vessels. FIG.1B generally illustrates efferent nerves from vasomotor centers. Anefferent nerve conveys impulses away from a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, and increases digestion in the smallintention, increases urine secretion, and contracts the wall and relaxesthe sphincter of the bladder. The functions associated with thesympathetic and parasympathetic nervous systems are many and can becomplexly integrated with each other. Thus, an indiscriminatestimulation of the sympathetic and/or parasympathetic nervous systems toachieve a desired response, such as vasodilation, in one physiologicalsystem may also result in an undesired response in other physiologicalsystems.

Baroreflex is a reflex triggered by stimulation of a baroreceptor. Abaroreceptor includes any sensor of pressure changes, such as sensorynerve endings in the wall of the auricles of the heart, cardiac fatpads, vena cava, aortic arch and carotid sinus, that is sensitive tostretching of the wall resulting from increased pressure from within,and that functions as the receptor of the central reflex mechanism thattends to reduce that pressure. Additionally, a baroreceptor includesafferent nerve trunks, such as the vagus, aortic and carotid nerves,leading from the sensory nerve endings. Stimulating baroreceptorsinhibits sympathetic nerve activity (stimulates the parasympatheticnervous system) and reduces systemic arterial pressure by decreasingperipheral vascular resistance and cardiac contractility. Baroreceptorsare naturally stimulated by internal pressure and the stretching of thearterial wall.

Some aspects of the present subject matter locally stimulate specificnerve endings in arterial walls rather than stimulate afferent nervetrunks in an effort to stimulate a desire response (e.g. reducedhypertension) while reducing the undesired effects of indiscriminatestimulation of the nervous system. For example, some embodimentsstimulate baroreceptor sites in the pulmonary artery. Some embodimentsof the present subject matter involve stimulating either baroreceptorsites or nerve endings in the aorta, the chambers of the heart, the fatpads of the heart, and some embodiments of the present subject matterinvolve stimulating an afferent nerve trunk, such as the vagus, carotidand aortic nerves. Some embodiments stimulate afferent nerve trunksusing a cuff electrode, and some embodiments stimulate afferent nervetrunks using an intravascular lead positioned in a blood vesselproximate to the nerve, such that the electrical stimulation passesthrough the vessel wall to stimulate the afferent nerve trunk.

FIGS. 2A-2C illustrate a heart. As illustrated in FIG. 2A, the heart 201includes a superior vena cava 202, an aortic arch 203, and a pulmonaryartery 204, and is useful to provide a contextual relationship with theillustrations in FIGS. 3-5. As is discussed in more detail below, thepulmonary artery 204 includes baroreceptors. A lead is capable of beingintravascularly inserted through a peripheral vein and through thetricuspid valve into the right ventricle of the heart (not expresslyshown in the figure) similar to a cardiac pacemaker lead, and continuefrom the right ventricle through the pulmonary valve into the pulmonaryartery. A portion of the pulmonary artery and aorta are proximate toeach other. Various embodiments stimulate baroreceptors in the aortausing a lead intravascularly positioned in the pulmonary artery. Thus,according to various aspects of the present subject matter, thebaroreflex is stimulated in or around the pulmonary artery by at leastone electrode intravascularly inserted into the pulmonary artery.Alternatively, a wireless stimulating device, with or without pressuresensing capability, may be positioned via catheter into the pulmonaryartery. Control of stimulation and/or energy for stimulation may besupplied by another implantable or external device via ultrasonic,electromagnetic or a combination thereof. Aspects of the present subjectmatter provide a relatively noninvasive surgical technique to implant abaroreceptor stimulator intravascularly into the pulmonary artery.

FIGS. 2B-2C illustrate the right side and left side of the heart,respectively, and further illustrate cardiac fat pads which have nerveendings that function as baroreceptor sites. FIG. 2B illustrates theright atrium 267, right ventricle 268, sinoatrial node 269, superiorvena cava 202, inferior vena cava 270, aorta 271, right pulmonary veins272, and right pulmonary artery 273. FIG. 2B also illustrates a cardiacfat pad 274 between the superior vena cava and aorta. Baroreceptor nerveendings in the cardiac fat pad 274 are stimulated in some embodimentsusing an electrode screwed into the fat pad, and are stimulated in someembodiments using an intravenously-fed lead proximately positioned tothe fat pad in a vessel such as the right pulmonary artery or superiorvena cava, for example. FIG. 2C illustrates the left atrium 275, leftventricle 276, right atrium 267, right ventricle 268, superior vena cava202, inferior vena cava 270, aorta 271, right pulmonary veins 272, leftpulmonary vein 277, right pulmonary artery 273, and coronary sinus 278.FIG. 2C also illustrates a cardiac fat pad 279 located proximate to theright cardiac veins and a cardiac fat pad 280 located proximate to theinferior vena cava and left atrium. Baroreceptor nerve endings in thefat pad 279 are stimulated in some embodiments using an electrodescrewed into the fat pad 279, and are stimulated in some embodimentsusing an intravenously-fed lead proximately positioned to the fat pad ina vessel such as the right pulmonary artery 273 or right pulmonary vein272, for example. Baroreceptors in the 280 are stimulated in someembodiments using an electrode screwed into the fat pad, and arestimulated in some embodiments using an intravenously-fed leadproximately positioned to the fat pad in a vessel such as the inferiorvena cava 270 or coronary sinus or a lead in the left atrium 275, forexample.

FIG. 3 illustrates baroreceptors in the area of the carotid sinuses 305,aortic arch 303 and pulmonary artery 304. The aortic arch 303 andpulmonary artery 304 were previously illustrated with respect to theheart in FIG. 2A. As illustrated in FIG. 3, the vagus nerve 306 extendsand provides sensory nerve endings 307 that function as baroreceptors inthe aortic arch 303, in the carotid sinus 305 and in the common carotidartery 310. The glossopharyngeal nerve 308 provides nerve endings 309that function as baroreceptors in the carotid sinus 305. These nerveendings 307 and 309, for example, are sensitive to stretching of thewall resulting from increased pressure from within. Activation of thesenerve endings reduce pressure. Although not illustrated in the figures,the fat pads and the atrial and ventricular chambers of the heart alsoinclude baroreceptors. Cuffs have been placed around afferent nervetrunks, such as the vagal nerve, leading from baroreceptors to vasomotorcenters to stimulate the baroreflex. According to various embodiments ofthe present subject matter, afferent nerve trunks can be stimulatedusing a cuff or intravascularly-fed lead positioned in a blood vesselproximate to the afferent nerves.

FIG. 4 illustrates baroreceptors in and around a pulmonary artery 404.The superior vena cava 402 and the aortic arch 403 are also illustrated.As illustrated, the pulmonary artery 404 includes a number ofbaroreceptors 411, as generally indicated by the dark area. Furthermore,a cluster of closely spaced baroreceptors is situated near theattachment of the ligamentum arteriosum 412. FIG. 4 also illustrates theright ventricle 413 of the heart, and the pulmonary valve 414 separatingthe right ventricle 413 from the pulmonary artery 404. According tovarious embodiments of the present subject matter, a lead is insertedthrough a peripheral vein and threaded through the tricuspid valve intothe right ventricle, and from the right ventricle 413 through thepulmonary valve 414 and into the pulmonary artery 404 to stimulatebaroreceptors in and/or around the pulmonary artery. In variousembodiments, for example, the lead is positioned to stimulate thecluster of baroreceptors near the ligamentum arteriosum 412. FIG. 5illustrates baroreceptor fields 512 in the aortic arch 503, near theligamentum arteriosum and the trunk of the pulmonary artery 504. Someembodiments position the lead in the pulmonary artery to stimulatebaroreceptor sites in the aorta and/or fat pads, such as are illustratedin FIGS. 2B-2C.

FIG. 6 illustrates a known relationship between respiration 615 andblood pressure 616 when the left aortic nerve is stimulated. When thenerve is stimulated at 617, the blood pressure 616 drops, and therespiration 615 becomes faster and deeper, as illustrated by the higherfrequency and amplitude of the respiration waveform. The respiration andblood pressure appear to return to the pre-stimulated state inapproximately one to two minutes after the stimulation is removed.Various embodiments of the present subject matter use this relationshipbetween respiration and blood pressure by using respiration as asurrogate parameter for blood pressure.

FIG. 7 illustrates a known blood pressure response to carotid nervestimulation in a hypertensive dog during 6 months of intermittentcarotid nerve stimulation. The figure illustrates that the bloodpressure of a stimulated dog 718 is significantly less than the bloodpressure of a control dog 719 that also has high blood pressure. Thus,intermittent stimulation is capable of triggering the baroreflex toreduce high blood pressure.

Baroreflex Stimulator Systems

Various embodiments of the present subject matter relate to baroreflexstimulator systems. Such baroreflex stimulation systems are alsoreferred to herein as neural stimulator (NS) devices or components.Examples of neural stimulators include anti-hypertension (AHT) devicesor AHT components that are used to treat hypertension. Variousembodiments of the present subject matter include stand-aloneimplantable baroreceptor stimulator systems, include implantable devicesthat have integrated NS and cardiac rhythm management (CRM) components,and include systems with at least one implantable NS device and animplantable CRM device capable of communicating with each other eitherwirelessly or through a wire lead connecting the implantable devices.Integrating NS and CRM functions that are either performed in the sameor separate devices improves aspects of the NS therapy and cardiactherapy by allowing these therapies to work together intelligently.

FIG. 8 illustrates a system 820 including an implantable medical device(IMD) 821 and a programmer 822, according to various embodiments of thepresent subject matter. Various embodiments of the IMD 821 includeneural stimulator functions only, and various embodiments include acombination of NS and CRM functions. Some embodiments of the neuralstimulator provide AHT functions. The programmer 822 and the IMD 821 arecapable of wirelessly communicating data and instructions. In variousembodiments, for example, the programmer 822 and IMD 821 use telemetrycoils to wirelessly communicate data and instructions. Thus, theprogrammer can be used to adjust the programmed therapy provided by theIMD 821, and the IMD can report device data (such as battery and leadresistance) and therapy data (such as sense and stimulation data) to theprogrammer using radio telemetry, for example. According to variousembodiments, the IMD 821 stimulates baroreceptors to provide NS therapysuch as AHT therapy. Various embodiments of the IMD 821 stimulatebaroreceptors in the pulmonary artery using a lead fed through the rightventricle similar to a cardiac pacemaker lead, and further fed into thepulmonary artery. According to various embodiments, the IMD 821 includesa sensor to sense ANS activity. Such a sensor can be used to performfeedback in a closed loop control system. For example, variousembodiments sense surrogate parameters, such as respiration and bloodpressure, indicative of ANS activity. According to various embodiments,the IMD further includes cardiac stimulation capabilities, such aspacing and defibrillating capabilities in addition to the capabilitiesto stimulate baroreceptors and/or sense ANS activity.

FIG. 9 illustrates an implantable medical device (IMD) 921 such as theIMD 821 shown in the system 820 of FIG. 8, according to variousembodiments of the present subject matter. The illustrated IMD 921performs NS functions. Some embodiments of the illustrated IMD 921performs an AHT function, and thus illustrates an implantable AHTdevice. The illustrated device 921 includes controller circuitry 923 anda memory 924. The controller circuitry 923 is capable of beingimplemented using hardware, software, and combinations of hardware andsoftware. For example, according to various embodiments, the controllercircuitry 923 includes a processor to perform instructions embedded inthe memory 924 to perform functions associated with NS therapy such asAHT therapy. For example, the illustrated device 921 further includes atransceiver 925 and associated circuitry for use to communicate with aprogrammer or another external or internal device. Various embodimentshave wireless communication capabilities. For example, some transceiverembodiments use a telemetry coil to wirelessly communicate with aprogrammer or another external or internal device.

The illustrated device 921 further includes baroreceptor stimulationcircuitry 926. Various embodiments of the device 921 also includessensor circuitry 927. One or more leads are able to be connected to thesensor circuitry 927 and baroreceptor stimulation circuitry 926. Thebaroreceptor stimulation circuitry 926 is used to apply electricalstimulation pulses to desired baroreceptors sites, such as baroreceptorsites in the pulmonary artery, through one or more stimulationelectrodes. The sensor circuitry 927 is used to detect and process ANSnerve activity and/or surrogate parameters such as blood pressure,respiration and the like, to determine the ANS activity.

According to various embodiments, the stimulator circuitry 926 includesmodules to set any one or any combination of two or more of thefollowing pulse features: the amplitude 928 of the stimulation pulse,the frequency 929 of the stimulation pulse, the burst frequency 930 orduty cycle of the pulse, and the wave morphology 931 of the pulse.Examples of wave morphology include a square wave, triangle wave,sinusoidal wave, and waves with desired harmonic components to mimicwhite noise such as is indicative of naturally-occurring baroreflexstimulation.

FIGS. 10A-10C illustrate a baroreceptor stimulation lead with anintegrated pressure sensor (IPS), according to various embodiments ofthe present subject matter. Although not drawn to scale, theseillustrated leads 1032A, 1032B and 1032C include an IPS 1033 with abaroreceptor stimulator electrode 1034 to monitor changes in bloodpressure, and thus the effect of the baroreceptor stimulation. Theselead illustrations should not be read as limiting other aspects andembodiments of the present subject matter. In various embodiments, forexample, micro-electrical mechanical systems (MEMS) technology is usedto sense the blood pressure. Some sensor embodiments determine bloodpressure based on a displacement of a membrane.

FIGS. 10A-10C illustrate an IPS on a lead. Some embodiments implant anIPS in an IMD or NS device. The stimulator and sensor functions can beintegrated, even if the stimulator and sensors are located in separateleads or positions.

The lead 1032A illustrated in FIG. 10A includes a distally-positionedbaroreceptor stimulator electrode 1034 and an IPS 1033. This lead, forexample, is capable of being intravascularly introduced to stimulate abaroreceptor site, such as the baroreceptor sites in the pulmonaryartery, aortic arch, ligamentum arteriosum, the coronary sinus, in theatrial and ventricular chambers, and/or in cardiac fat pads.

The lead 1032B illustrated in FIG. 10B includes a tip electrode 1035, afirst ring electrode 1036, second ring electrode 1034, and an IPS 1033.This lead may be intravascularly inserted into or proximate to chambersof the heart and further positioned proximate to baroreceptor sites suchthat at least some of the electrodes 1035, 1036 and 1034 are capable ofbeing used to pace or otherwise stimulate the heart, and at least someof the electrodes are capable of stimulating at least one baroreceptorsite. The IPS 1033 is used to sense the blood pressure. In variousembodiments, the IPS is used to sense the blood pressure in the vesselproximate to the baroreceptor site selected for stimulation.

The lead 1032C illustrated in FIG. 10C includes a distally-positionedbaroreceptor stimulator electrode 1034, an IPS 1033 and a ring electrode1036. This lead 1032C may, for example, be intravascularly inserted intothe right atrium and ventricle, and then through the pulmonary valveinto the pulmonary artery. Depending on programming in the device, theelectrode 1036 can be used to pace and/or sense cardiac activity, suchas that which may occur within the right ventricle, and the electrode1034 and IPS 1033 are located near baroreceptors in or near thepulmonary artery to stimulate and sense, either directly or indirectlythrough surrogate parameters, baroreflex activity.

Thus, various embodiments of the present subject matter provide animplantable NS device that automatically modulates baroreceptorstimulation using an IPS. Integrating the pressure sensor into the leadprovides localized feedback for the stimulation. This localized sensingimproves feedback control. For example, the integrated sensor can beused to compensate for inertia of the baroreflex such that the target isnot continuously overshot. According to various embodiments, the devicemonitors pressure parameters such as mean arterial pressure, systolicpressure, diastolic pressure and the like. As mean arterial pressureincreases or remains above a programmable target pressure, for example,the device stimulates baroreceptors at an increased rate to reduce bloodpressure and control hypertension. As mean arterial pressure decreasestowards the target pressure, the device responds by reducingbaroreceptor stimulation. In various embodiments, the algorithm takesinto account the current metabolic state (cardiac demand) and adjustsneural stimulation accordingly. A NS device having an IPS is able toautomatically modulate baroreceptor stimulation, which allows animplantable NS device to determine the level of hypertension in thepatient and respond by delivering the appropriate level of therapy.However, it is noted that other sensors, including sensors that do notreside in an NS or neural stimulator device, can be used to provideclose loop feedback control.

FIG. 11 illustrates an implantable medical device (IMD) 1121 such asshown at 821 in FIG. 8 having an anti-hypertension (AHT) component 1137and cardiac rhythm management (CRM) component 1138, according to variousembodiments of the present subject matter. The illustrated device 1121includes a controller 1123 and a memory 1124. According to variousembodiments, the controller 1123 includes hardware, software, or acombination of hardware and software to perform the baroreceptorstimulation and CRM functions. For example, the programmed therapyapplications discussed in this disclosure are capable of being stored ascomputer-readable instructions embodied in memory and executed by aprocessor. According to various embodiments, the controller 1123includes a processor to execute instructions embedded in memory toperform the baroreceptor stimulation and CRM functions. The illustrateddevice 1121 further includes a transceiver 1125 and associated circuitryfor use to communicate with a programmer or another external or internaldevice. Various embodiments include a telemetry coil.

The CRM therapy section 1138 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The CRM therapy section includes a pulsegenerator 1139 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry1140 to detect and process sensed cardiac signals. An interface 1141 isgenerally illustrated for use to communicate between the controller 1123and the pulse generator 1139 and sense circuitry 1140. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 1137 includes components, under the control ofthe controller, to stimulate a baroreceptor and/or sense ANS parametersassociated with nerve activity or surrogates of ANS parameters such asblood pressure and respiration. Three interfaces 1142 are illustratedfor use to provide ANS therapy. However, the present subject matter isnot limited to a particular number interfaces, or to any particularstimulating or sensing functions. Pulse generators 1143 are used toprovide electrical pulses to an electrode for use to stimulate abaroreceptor site. According to various embodiments, the pulse generatorincludes circuitry to set, and in some embodiments change, the amplitudeof the stimulation pulse, the frequency of the stimulation pulse, theburst frequency of the pulse, and the morphology of the pulse such as asquare wave, triangle wave, sinusoidal wave, and waves with desiredharmonic components to mimic white noise or other signals. Sensecircuits 1144 are used to detect and process signals from a sensor, suchas a sensor of nerve activity, blood pressure, respiration, and thelike. The interfaces 1142 are generally illustrated for use tocommunicate between the controller 1123 and the pulse generator 1143 andsense circuitry 1144. Each interface, for example, may be used tocontrol a separate lead. Various embodiments of the NS therapy sectiononly include a pulse generator to stimulate baroreceptors. For example,the NS therapy section provides AHT therapy.

An aspect of the present subject matter relates to achronically-implanted stimulation system specially designed to treathypertension by monitoring blood pressure and stimulating baroreceptorsto activate the baroreceptor reflex and inhibit sympathetic dischargefrom the vasomotor center. Baroreceptors are located in variousanatomical locations such as the carotid sinus and the aortic arch.Other baroreceptor locations include the pulmonary artery, including theligamentum arteriosum, and sites in the atrial and ventricular chambers.In various embodiments, the system is integrated into apacemaker/defibrillator or other electrical stimulator system.Components of the system include a high-frequency pulse generator,sensors to monitor blood pressure or other pertinent physiologicalparameters, leads to apply electrical stimulation to baroreceptors,algorithms to determine the appropriate time to administer stimulation,and algorithms to manipulate data for display and patient management.

Various embodiments relate to a system that seeks to deliverelectrically mediated NS therapy, such as AHT therapy, to patients.Various embodiments combine a “stand-alone” pulse generator with aminimally invasive, unipolar lead that directly stimulates baroreceptorsin the vicinity of the heart, such as in the pulmonary artery. Thisembodiment is such that general medical practitioners lacking the skillsof specialist can implant it. Various embodiments incorporate a simpleimplanted system that can sense parameters indicative of blood pressure.This system adjusts the therapeutic output (waveform amplitude,frequency, etc.) so as to maintain a desired quality of life. In variousembodiments, an implanted system includes a pulse generating device andlead system, the stimulating electrode of which is positioned nearendocardial baroreceptor tissues using transvenous implant technique(s).Another embodiment includes a system that combines NS therapy withtraditional bradyarrhythmia, tachyarrhythmia, and/or congestive heartfailure (CHF) therapies. Some embodiments use an additional“baroreceptor lead” that emerges from the device header and is pacedfrom a modified traditional pulse generating system. In anotherembodiment, a traditional CRM lead is modified to incorporate proximalelectrodes that are naturally positioned near baroreceptor sites. Withthese leads, distal electrodes provide CRM therapy and proximateelectrodes stimulate baroreceptors.

A system according to these embodiments can be used to augment partiallysuccessful treatment strategies. As an example, undesired side effectsmay limit the use of some pharmaceutical agents. The combination of asystem according to these embodiments with reduced drug doses may beparticularly beneficial.

According to various embodiments, the lead(s) and the electrode(s) onthe leads are physically arranged with respect to the heart in a fashionthat enables the electrodes to properly transmit pulses and sensesignals from the heart, and with respect to baroreceptors to stimulatethe baroreflex. As there may be a number of leads and a number ofelectrodes per lead, the configuration can be programmed to use aparticular electrode or electrodes. According to various embodiments,the baroreflex is stimulated by stimulating afferent nerve trunks.

FIG. 12 illustrates a system 1220 including a programmer 1222, animplantable neural stimulator (NS) device 1237 and an implantablecardiac rhythm management (CRM) device 1238, according to variousembodiments of the present subject matter. Various aspects involve amethod for communicating between an NS device 1237, such as an AHTdevice, and a CRM device 1238 or other cardiac stimulator. In variousembodiments, this communication allows one of the devices 1237 or 1238to deliver more appropriate therapy (i.e. more appropriate NS therapy orCRM therapy) based on data received from the other device. Someembodiments provide on-demand communications. In various embodiments,this communication allows each of the devices 1237 and 1238 to delivermore appropriate therapy (i.e. more appropriate NS therapy and CRMtherapy) based on data received from the other device. The illustratedNS device 1237 and the CRM device 1238 are capable of wirelesslycommunicating with each other, and the programmer is capable ofwirelessly communicating with at least one of the NS and the CRM devices1237 and 1238. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.

In some embodiments, the NS device 1237 stimulates the baroreflex toprovide NS therapy, and senses ANS activity directly or using surrogateparameters, such as respiration and blood pressure, indicative of ANSactivity. The CRM device 1238 includes cardiac stimulation capabilities,such as pacing and defibrillating capabilities. Rather than providingwireless communication between the NS and CRM devices 1237 and 1238,various embodiments provide a communication cable or wire, such as anintravenously-fed lead, for use to communicate between the NS device1237 and the CRM device 1238.

FIG. 13 illustrates an implantable neural stimulator (NS) device 1337such as shown at 1237 in the system of FIG. 12, according to variousembodiments of the present subject matter. FIG. 14 illustrates animplantable cardiac rhythm management (CRM) device 1438 such as shown at1238 in the system of FIG. 12, according to various embodiments of thepresent subject matter. Functions of the components for the NS device1337 were previously discussed with respect to FIGS. 9 and 11 (the NScomponent 1137), and functions of the components for the CRM device 1238were previously discussed with respect to FIG. 11 (the CRM component1138). In the interest of brevity, these discussions with respect to theNS and CRM functions are not repeated here. Various embodiments of theNS and CRM devices include wireless transceivers 1325 and 1425,respectively, to wirelessly communicate with each other. Variousembodiments of the NS and CRM devices include a telemetry coil orultrasonic transducer to wirelessly communicate with each other.

According to various embodiments, for example, the NS device is equippedwith a telemetry coil, allowing data to be exchanged between it and theCRM device, allowing the NS device to modify therapy based onelectrophysiological parameters such as heart rate, minute ventilation,atrial activation, ventricular activation, and cardiac events. Inaddition, the CRM device modifies therapy based on data received fromthe NS device, such as mean arterial pressure, systolic and diastolicpressure, and baroreceptors stimulation rate.

Some NS device embodiments are able to be implanted in patients withexisting CRM devices, such that the functionality of the NS device isenhanced by receiving physiological data that is acquired by the CRMdevice. The functionality of two or more implanted devices is enhancedby providing communication capabilities between or among the implanteddevices. In various embodiments, the functionality is further enhancedby designing the devices to wirelessly communicate with each other.

FIG. 15 illustrates a programmer 1522, such as the programmer 822 and1222 illustrated in the systems of FIGS. 8 and 12, or other externaldevice to communicate with the implantable medical device(s) 1237 and/or1238, according to various embodiments of the present subject matter. Anexample of another external device includes Personal Digital Assistants(PDAs) or personal laptop and desktop computers in an Advanced PatientManagement (APM) system. The illustrated device 1522 includes controllercircuitry 1545 and a memory 1546. The controller circuitry 1545 iscapable of being implemented using hardware, software, and combinationsof hardware and software. For example, according to various embodiments,the controller circuitry 1545 includes a processor to performinstructions embedded in the memory 1546 to perform a number offunctions, including communicating data and/or programming instructionsto the implantable devices. The illustrated device 1522 further includesa transceiver 1547 and associated circuitry for use to communicate withan implantable device. Various embodiments have wireless communicationcapabilities. For example, various embodiments of the transceiver 1547and associated circuitry include a telemetry coil for use to wirelesslycommunicate with an implantable device. The illustrated device 1522further includes a display 1548, input/output (I/O) devices 1549 such asa keyboard or mouse/pointer, and a communications interface 1550 for useto communicate with other devices, such as over a communication network.

Programmed Therapy Applications

NS and/or CRM functions of a system, whether implemented in two separateand distinct implantable devices or integrated as components into oneimplantable device, includes processes for performing NS and/or CRMtherapy or portions of the therapy. In some embodiments, the NS therapyprovides AHT therapy. These processes can be performed by a processorexecuting computer-readable instructions embedded in memory, forexample. These therapies include a number of applications, which havevarious processes and functions, some of which are identified anddiscussed below. The processes and functions of these therapies are notnecessarily mutually exclusive, as some embodiments of the presentsubject matter include combinations of two or more of thebelow-identified processes and functions.

Accounting for Neural Stimulation to Accurately Sense Signals

FIGS. 16A-16D illustrate a system and methods to prevent interferencebetween electrical stimulation from an neural stimulator (NS) device andsensing by a cardiac rhythm management (CRM) device, according tovarious embodiments of the present subject matter. Neural stimulation isaccounted for to improve the ability to sense signals, and thus reduceor eliminate false positives associated with detecting a cardiac event.The NS device includes an AHT device in some embodiments. For example,the NS device communicates with and prevents or otherwise compensatesfor baroreflex stimulation such that the CRM device does notunintentionally react to the baroreflex stimulation, according to someembodiments. Some embodiments automatically synchronize the baroreflexstimulation with an appropriate refraction in the heart. For example,some systems automatically synchronize stimulation of baroreceptors inor around the pulmonary artery with atrial activation. Thus, thefunctions of the CRM device are not adversely affected by detectingfar-field noise generated by the baroreflex stimulation, even when thebaroreflex stimulations are generated near the heart and the CRM sensorsthat detect the cardiac electrical activation.

FIG. 16A generally illustrates a system 1654 that includes NS functions1651 (such as may be performed by a NS device or a NS component in anintegrated NS/CRM device), CRM functions 1652 (such as may be performedby a CRM device or a CRM component in an integrated NS/CRM device) andcapabilities to communicate 1653 between the NS and CRM functions. Theillustrated communication is bidirectional wireless communication.However, the present subject matter also contemplates unidirectionalcommunication, and further contemplates wired communication.Additionally, the present subject matter contemplates that the NS andCRM functions 1651 and 1652 can be integrated into a single implantabledevice such that the communication signal is sent and received in thedevice, or in separate implantable devices. Although baroreflexstimulation as part of neural stimulation is specifically discussed,this aspect of the present subject matter is also applicable to prevent,or account or other wise compensate for, unintentional interferencedetectable by a sensor and generated from other electrical stimulators.

FIG. 16B illustrates a process where CRM functions do notunintentionally react to baroreflex stimulation, according to variousembodiments. FIG. 16B illustrates a process where the NS device orcomponent 1651 sends an alert or otherwise informs the CRM device orcomponent when baroreceptors are being electrically stimulated. In theillustrated embodiment, the NS device/component determines at 1655 ifelectrical stimulation, such as baroreflex stimulation, is to beapplied. When electrical stimulation is to be applied, the NS device orcomponent 1651 sends at 1656 an alert 1657 or otherwise informs the CRMdevice or component 1652 of the electrical stimulation. At 1658, theelectrical stimulation is applied by the NS device/component. At 1659CRM therapy, including sensing, is performed. At 1660, the CRMdevice/component determines whether an alert 1657 has been received fromthe NS device/component. If an alert has been received, an eventdetection algorithm is modified at 1661 to raise a detection threshold,provide a blackout or blanking window, or otherwise prevent theelectrical stimulation in the NS device or component from beingmisinterpreted as an event by the CRM device/component.

FIG. 16C illustrates a process where CRM functions do notunintentionally react to baroreflex stimulation, according to variousembodiments. The CRM device/component 1652 determines a refractoryperiod for the heart at 1662. At 1663, if a refractory period isoccurring or is expected to occur in a predictable amount of time, anenable 1664 corresponding to the refractory is provided to the NSdevice/component 1651. The AHT device/component 1651 determines ifelectrical stimulation is desired at 1655. When desired, the AHTdevice/component applies electrical stimulation during a refractoryperiod at 1666, as controlled by the enable signal 1664. FIG. 16Dillustrates a refractory period at 1667 in a heart and a baroreflexstimulation 1668, and further illustrates that baroreflex stimulation isapplied during the refractory period.

A refractory period includes both absolute and relative refractoryperiods. Cardiac tissue is not capable of being stimulated during theabsolute refractory period. The required stimulation threshold during anabsolute refractory period is basically infinite. The relativerefractory period occurs after the absolute refractory period. Duringthe relative refractory period, as the cardiac tissue begins torepolarize, the stimulation threshold is initially very high and dropsto a normal stimulation threshold by the end of the relative refractoryperiod. Thus, according to various embodiments, a neural stimulatorapplies neural stimulation during either the absolute refractory periodor during a portion of the relative refractory period corresponding asufficiently high stimulation threshold to prevent the neuralstimulation from capturing cardiac tissue.

Various embodiments of the present subject matter relate to a method ofsensing atrial activation and confining pulmonary artery stimulation tothe atrial refractory period, preventing unintentional stimulation ofnearby atrial tissue. An implantable baroreceptor stimulation devicemonitors atrial activation with an atrial sensing lead. A lead in thepulmonary artery stimulates baroreceptors in the vessel wall. However,instead of stimulating these baroreceptors continuously, the stimulationof baroreceptors in the pulmonary artery occurs during the atrialrefractory period to avoid capturing nearby atrial myocardium,maintaining the intrinsic atrial rate and activation. Variousembodiments of the present subject matter combine an implantable devicefor stimulating baroreceptors in the wall of the pulmonary artery withthe capability for atrial sensing. Various embodiments stimulatebaroreceptors in the cardiac fat pads, in the heart chambers, and/orafferent nerves.

FIG. 17 illustrates a system to modulate baroreflex stimulation,according to various embodiments of the present subject matter. Theillustrated system 1769 includes a baroreflex stimulator 1751, such asstimulator to stimulate baroreceptors in and around the pulmonaryartery. The baroreflex stimulator can be included in a stand-alone NSdevice or as a NS component in an integrated NS/CRM device, for example.The illustrated stimulator 1751 includes a modulator 1769 for use toselectively increase and decrease the applied baroreflex stimulation.According to various embodiments, the modulator 1769 includes any one ofthe following modules: a module 1770 to change the amplitude of thestimulation pulse; a module 1771 to change the frequency of thestimulation pulse; and a module 1772 to change the burst frequency ofthe stimulation pulse. The burst frequency can also be referred to as aduty cycle. According to various embodiments, the modulator 1769includes functions for the various combinations of two or more of themodules 1770, 1771 and 1772. Additionally, a stimulator can include awaveform generator capable of providing different waveforms in responseto a control signal.

Various embodiments of the system include any one or any combination ofa cardiac activity monitor 1773, an adverse event detector 1774, arespiration monitor 1775, and a circadian rhythm template 1776 which arecapable of controlling the modulator 1769 of the stimulator 1759 toappropriately apply a desired level of baroreflex stimulation. Each ofthese 1773, 1774, 1775, and 1776 are associated with a method tomodulate a baroreflex signal. According to various embodiments, thesystem includes means to modulate a baroreflex signal based on thefollowing parameters or parameter combinations: cardiac activity (1773);an adverse event (1774); respiration (1775); circadian rhythm (1776);cardiac activity (1773) and an adverse event (1774); cardiac activity(1773) and respiration (1775); cardiac activity (1773) and circadianrhythm (1776); an adverse event (1774) and respiration (1775); anadverse event (1774) and circadian rhythm (1776); respiration (1775) andcircadian rhythm (1776); cardiac activity (1773), an adverse event(1774), and respiration (1775); cardiac activity (1773), an adverseevent (1774), and circadian rhythm (1776); cardiac activity (1773),respiration (1775), and circadian rhythm (1776); an adverse event(1774), respiration (1775) and circadian rhythm (1776); and cardiacactivity (1773), an adverse event (1774), respiration (1775) andcircadian rhythm (1776). According to various embodiments, the systemincludes means to automatically adjust baroreflex stimulation usingheart rate as a feedback mechanism to provide a desired effect on theheart rate.

The stimulation can be applied to an afferent nerve trunk such as thevagal nerve using a cuff electrode or an intravascularly-fed leadpositioned proximate to the nerve trunk. The stimulation can be appliedto baroreceptor sites such are located in the pulmonary artery, aorticarch, and carotid sinus, for example, using intravenously-fed leads. Thestimulation can be applied to baroreceptor sites located in cardiac fatpads using intravenously-fed leads or by screwing electrodes into thefat pads. Embodiments of the cardiac activity detector 1774, forexample, include any one or any combination of a heart rate monitor1777, a minute ventilation monitor 1778, and an acceleration monitor1779. The respiration monitor 1775 functions as a surrogate formonitoring blood pressure. Embodiments of the respiration monitor 1775include any one or any combination of a tidal volume monitor 1780 and aminute ventilation module 1781. Embodiments of the circadian rhythmtemplate 1776 include any one or combination of a custom generatedtemplate 1782 and a preprogrammed template 1783. These embodiments arediscussed in more detail below with respect to FIGS. 18A-18C, 19A-19B,20A-20B, 21A-21E, 22 and 23A-23C.

Various embodiments use the circadian rhythm template to provide AHTtherapy. Various embodiments use the circadian rhythm template toprovide apnea therapy.

Modulation of Baroreflex Stimulation Based on Systolic Intervals

Activation of the sympathetic or parasympathetic nervous systems isknown to alter certain systolic intervals, primarily the pre-ejectionperiod (PEP), the time interval between sensed electrical activitywithin the ventricle (e.g. sensing of the “R” wave) and the onset ofventricular ejection of blood. The PEP may be measured from the sensedelectrical event to the beginning of pressure increase in the pulmonaryartery, using a pulmonary arterial pressure sensor, or may be measuredto the beginning of an increase in intracardiac impedance, accompanyinga decrease in ventricular volume during ejection, using electrodespositioned in the right or spanning the left ventricle. At rest, asdetermined by heart rate or body activity measured with an accelerometerfor example, neural stimulation is modulated to maintain PEP in apre-programmed range. A sudden decrease in PEP indicates an increase insympathetic tone associated with exercise or emotional stress. Thiscondition may be used to decrease neural stimulation permittingincreases in heart rate and contractility necessary to meet metabolicdemand. In like manner, a subsequent dramatic lengthening of PEP marksthe end of increased metabolic demand. At this time control of bloodpressure with neural stimulation could recommence.

Modulation of Baroreflex Stimulation Based on Cardiac Activity

The present subject matter describes a method of automaticallymodulating baroreceptor stimulation based on cardiac activity, such ascan be determined by the heart rate, minute ventilation, accelerationand combinations thereof. The functionality of a device for electricallystimulating baroreceptors is enhanced by applying at least a relativelyhigh baropacing rate during rest when metabolic demand is relativelylow, and progressively less baropacing during physical exertion asmetabolic demand increases. Indices of cardiac activity are used toautomatically modulate the electrical stimulation of baroreceptors,allowing an implantable anti-hypertension device to respond to changesin metabolic demand. According to various embodiments, a CRM device,such as a pacemaker, AICD or CRT devices, also has a baroreceptorstimulation lead. The device monitors cardiac activity through existingmethods using, for example, a blended sensor. A blended sensor includestwo sensors to measure parameters such as acceleration and minuteventilation. The output of the blended sensor represents a compositeparameter. Various NS and AHT therapies use composite parameters derivedfrom two or more sensed parameters as discussed within this disclosure.At rest (lower cardiac activity) the device stimulates baroreceptors ata higher rate, reducing blood pressure and controlling hypertension. Ascardiac activity increases, the device responds by temporarily reducingbaroreceptor stimulation. This results in a temporary increase in bloodpressure and cardiac output, allowing the body to respond to increasedmetabolic demand. For example, some embodiments provide baroreflexstimulation during rest and withdraw baroreflex stimulation duringexercise to match normal blood pressure response to exercise. A pressuretransducer can be used to determine activity. Furthermore, activity canbe sensed using sensors that are or have been used to drive rateadaptive pacing. Examples of such sensors include sensor to detect bodymovement, heart rate, QT interval, respiration rate, transthoracicimpedance, tidal volume, minute ventilation, body posture,electroencephalogram (EEG), electrocardiogram (ECG), electrooculogram(EOG), electromyogram (EMG), muscle tone, body temperature, pulseoximetry, time of day and pre-ejection interval from intracardiacimpedance.

Various embodiments of the cardiac activity monitor includes a sensor todetect at least one pressure parameter such as a mean arterialparameter, a pulse pressure determined by the difference between thesystolic and diastolic pressures, end systolic pressure (pressure at theend of the systole), and end diastolic pressure (pressure at the end ofthe diastole). Various embodiments of the cardiac activity monitorinclude a stroke volume monitor. Heart rate and pressure can be used toderive stroke volume. Various embodiments of the cardiac activitymonitor use at least one electrogram measurement to determine cardiacactivity. Examples of such electrogram measurements include the R-Rinterval, the P-R interval, and the QT interval. Various embodiments ofthe cardiac activity monitor use at least one electrocardiogram (ECG)measurement to determine cardiac activity.

FIGS. 18A-18C illustrate methods for modulating baroreceptor stimulationbased on a cardiac activity parameter, according to various embodimentsof the present subject matter. The cardiac activity can be determined bya CRM device, an NS device, or an implantable device with NS/CRMcapabilities. A first process 1884A for modulating baroreceptorstimulation based on cardiac activity is illustrated in FIG. 18A. At1885A the activity level is determined. According to variousembodiments, the determination of activity level is based on heart rate,minute ventilation, acceleration or any combination of heart rate,minute ventilation, acceleration. In the illustrated process, theactivity level has two defined binary levels (e.g. HI and LO). In someembodiments, the LO level includes no stimulation. It is determinedwhether the activity level is HI or LO. At 1886A, the baroreceptorstimulation level is set based on the determined activity level. A LOstimulation level is set if the activity level is determined to be HI,and a HI stimulation level is set if the activity level is determined tobe LO.

A second process 1884B for modulating baroreceptor stimulation based oncardiac activity is illustrated in FIG. 18B. At 1885B the activity levelis determined. According to various embodiments, the determination ofactivity level is based on heart rate, minute ventilation, accelerationor any combination of heart rate, minute ventilation, acceleration. Inthe illustrated process, the activity level has more than two definedlevels or n defined levels. It is determined whether the activity levelis level 1, level 2 . . . or level n. The activity level labelscorrespond to an increasing activity. At 1886B, the baroreceptorstimulation level is set based on the determined activity level.Available stimulation levels include level n . . . level 2 and level 1,where the stimulation level labels correspond to increasing stimulation.According to various embodiments, the selected baroreceptor stimulationlevel is inversely related to the determined activity level. Forexample, if it is determined that the cardiac activity level is at thehighest level n, then the stimulation level is set to the lowest leveln. If it determined that the stimulation level is at the first or secondto the lowest level, level 1 or level 2 respectively, then thestimulation level is set to the first or second to the highest level,level 1 or level 2 respectively.

Another process 1884C for modulating baroreceptor stimulation based oncardiac activity is illustrated in FIG. 18C. At 1887, an acquiredcardiac activity parameter is compared to a target activity parameter.If the acquired cardiac activity is lower than the target activityparameter, baroreceptor stimulation is increased at 1888. If theacquired cardiac activity is higher than the target activity parameter,baroreceptor stimulation is decreased at 1889. As discussed below withrespect to FIGS. 26A and 26B, various embodiments modulate or changebaroreceptor stimulation to achieve a desired effect on a heart rate oranother monitored cardiovascular parameter or a surrogate parameter forheart rate that increases and decreases with the heart rate. Forexample, various embodiments set the targeted heart rate duringstimulation to be a percentage (e.g. 5%, 10%, etc.) below a heart ratewithout stimulation; and various embodiments set the targeted heartduring stimulation to be a quantitative value (e.g. 5 bpm, 10 bpm, etc.)below a heart rate without stimulation. Such a system continues toprovide a desired stimulation level regardless of changes in the system,such as adaptation of the nervous system to stimulation, changes inelectrical impedance or other device characteristics associated with thestimulator, tissue encapsulation and fibrosis.

An aspect of the present subject matter relates to a method ofautomatically modulating the intensity of baroreceptor stimulation basedon respiration, as determined by tidal volume or minute ventilation.Instead of applying continuous baroreceptor stimulation, the NS devicemonitors the level of hypertension and delivers an appropriate level oftherapy, using respiration as a surrogate for blood pressure, allowingthe device to modulate the level of therapy. The present subject matteruses indices of respiration, such as impedance, to determined tidalvolume and minute ventilation and to automatically modulate baroreceptorstimulation. Thus, an implantable NS device is capable of determiningthe level of hypertension in the patient and respond by delivering anappropriate level of therapy. In various embodiments, an implantable NSdevice contains a sensor to measure tidal volume or minute ventilation.For example, various embodiments measure transthoracic impedance toobtain a rate of respiration. The device receives this data from a CRMdevice in some embodiments. The NS device periodically monitors theserespiration parameters. As respiration decreases or remains below aprogrammable target, the device stimulates baroreceptors at an increasedrate, reducing blood pressure and controlling hypertension. As meanarterial pressure increases towards the target, the device responds byreducing baroreceptor stimulation. In this way, the AHT devicecontinuously delivers an appropriate level of therapy.

FIGS. 19A-19B illustrate methods for modulating baroreceptor stimulationbased on a respiration parameter, according to various embodiments ofthe present subject matter. The respiration parameter can be determinedby a CRM device, an NS device, or an implantable device with NS/CRMcapabilities. One embodiment of a method for modulating baroreceptorstimulation based on a respiration parameter is illustrated at 1910A inFIG. 19A. The respiration level is determined at 1911, and thebaroreceptor stimulation level is set at 1912 based on the determinedrespiration level. According to various embodiments, the desiredbaropacing level is tuned at 1913. For example, one embodiment comparesan acquired parameter to a target parameter at 1914. The baropacing canbe increased at 1915 or decreased at 1916 based on the comparison of theacquired parameter to the target parameter.

One embodiment of a method for modulating baroreceptor stimulation basedon a respiration parameter is illustrated at 1910B in FIG. 19B. At 1916,a baroreflex event trigger occurs, which triggers an algorithm for abaroreflex stimulation process. At 1917, respiration is compared to atarget parameter. Baroreflex stimulation is increased at 1918 ifrespiration is below the target and is decreased at 1919 if respirationis above the target. According to various embodiments, the stimulationis not changed if the respiration falls within a blanking window.Various embodiments use memory to provide a hysteresis effect tostabilize the applied stimulation and the baroreflex response.Additionally, in various embodiments, the respiration target is modifiedduring the therapy based on various factors such as the time of day oractivity level. At 1920, it is determined whether to continue with thebaroreflex therapy algorithm based on, for example, sensed parameters orthe receipt of an event interrupt. If the baroreflex algorithm is tocontinue, then the process returns to 1917 where respiration is againcompared to a target parameter; else the baroreflex algorithm isdiscontinued at 1921.

Modulation of Baroreflex Stimulation Based on Adverse Event

Aspects of the present subject matter include a method of automaticallyincreasing baroreceptor stimulation upon detection of an adverse cardiacevent to increase vasodilatory response and potentially prevent orreduce myocardial ischemic damage. Various embodiments include afeedback mechanism in a cardiac rhythm management device (such as apacemaker, AICD or CRT device), which also has a stimulation lead forelectrically stimulating baroreceptors. The device monitors cardiacelectrical activity through existing methods. In the event of an adversecardiac event such as ventricular fibrillation (VF) and atrialfibrillation (AF), ventricular tachycardia (VT) and atrial tachycardia(AT) above a predefined rate, and dyspnea as detected by a minuteventilation sensor, angina, decompensation and ischemia, the deviceresponds by increasing baroreceptors stimulation to the maximallyallowable level. As a result, blood pressure is temporarily lowered,potentially preventing or reducing myocardial damage due to ischemia.The functionality of a device to treat hypertension can be expanded ifit can respond to adverse cardiac events by temporarily modulating theextent of baroreceptors stimulation. Event detection algorithmsautomatically modulate baroreceptors stimulation, allowing animplantable AHT device to respond to an adverse event by increasingbaroreceptors stimulation, potentially preventing or reducing myocardialischemic damage.

FIGS. 20A-20B illustrate methods for modulating baroreceptor stimulationbased on detection of an adverse event, according to various embodimentsof the present subject matter. The adverse event can be determined by aCRM device, an NS device, or an implantable device with NS/CRMcapabilities. FIG. 20A illustrates one embodiment for modulatingbaroreceptor stimulation based on detection of an adverse event. At2090A, it is determined whether an adverse event has been detected. Ifan adverse event has not been detected, normal baropacing (baropacingaccording to a normal routine) is performed at 2091A. If an adverseevent has been detected, enhanced baropacing is performed at 2092. Invarious embodiments, the maximum allowable baropacing is performed whenan adverse event is detected. Other baropacing procedures can beimplemented. For example, various embodiments normally apply baropacingstimulation and withholds baropacing therapy when an adverse event isdetected, and various embodiments normally withhold baropacing therapyand apply baropacing stimulation when an adverse event is detected. FIG.20B illustrate on embodiment for modulating baroreceptor stimulationbased on detection of an adverse event. At 2090B, it is determinedwhether an adverse event has been detected. If an adverse event has notbeen detected, normal baropacing (baropacing according to a normalroutine) is performed at 2091B. If an adverse event has been detected,the event is identified at 2093, and the appropriate baropacing for theidentified adverse event is applied at 2094. For example, proper bloodpressure treatment may be different for ventricular fibrillation thanfor ischemia. According to various embodiments, the desired baropacingis tuned for the identified event at 2095. For example, one embodimentcompares an acquired parameter to a target parameter at 2096. Thebaropacing can be increased at 2097 or decreased at 2098 based on thecomparison of the acquired parameter to the target parameter.

According to various embodiments, an adverse event includes detectableprecursors, such that therapy can be applied to prevent cardiacarrhythmia. In some embodiments, an adverse event includes both cardiacevents and non-cardiac events such as a stroke. Furthermore, someembodiments identify both arrhythmic and non-arrhythmic events asadverse events.

Modulation of Baroreflex Stimulation Based on Circadian Rhythm

An aspect of the present subject matter relates to a method forstimulating the baroreflex in hypertension patients so as to mimic thenatural fluctuation in blood pressure that occurs over a 24-hour period.Reflex reduction in hypertension is achieved during long-termbaroreceptor stimulation without altering the intrinsic fluctuation inarterial pressure. According to various embodiments, an implantabledevice is designed to stimulate baroreceptors in the carotid sinus,pulmonary artery, or aortic arch using short, high-frequency bursts(such as a square wave with a frequency within a range fromapproximately 20-150 Hz), for example. Some embodiments directlystimulate the carotid sinus nerve, aortic nerve or vagus nerve with acuff electrode. However, the bursts do not occur at a constant rate.Rather the stimulation frequency, amplitude, and/or burst frequencyrises and falls during the day mimicking the natural circadian rhythm.

Thus, various embodiments of a NS device accounts for naturalfluctuations in arterial pressure that occur in both normal andhypertensive individuals. Aside from activity-related changes in meanarterial pressure, subjects also exhibit a consistent fluctuation inpressure on a 24-hour cycle. A device which provides periodicbaroreceptor stimulation mimics the intrinsic circadian rhythm, allowingfor reflex inhibition of the systematic nervous system and reducedsystemic blood pressure without disturbing this rhythm. The presentsubject matter provides a pacing protocol which varies the baroreceptorstimulation frequency/amplitude in order to reduce mean arterialpressure without disturbing the intrinsic circadian rhythm.

FIGS. 21A-21E illustrate circadian rhythm. FIG. 21A illustrates thecircadian rhythm associated with mean arterial pressure for 24 hoursfrom noon to noon; FIG. 21B illustrates the circadian rhythm associatedwith heart rate for 24 hours from noon to noon; FIG. 21C illustrates thecircadian rhythm associated with percent change of stroke volume (SV %)for 24 hours from noon to noon; FIG. 21D illustrates the circadianrhythm associated with the percent change of cardiac output (CO) for 24hours from noon to noon; and FIG. 21E illustrates the circadian rhythmassociated with percent change of total peripheral resistance (TPR %),an index of vasodilation, for 24 hours from noon to noon. Variousembodiments graph absolute values, and various embodiments graph percentvalues. In these figures, the shaded portion represents night hours fromabout 10 PM to 7 AM, and thus represents rest or sleep times. Referringto FIGS. 21A and 21B, for example, it is evident that both the meanarterial pressure and the heart rate are lowered during periods of rest.A higher blood pressure and heart rate can adversely affect rest.Additionally, a lower blood pressure and heart rate during the day canadversely affect a person's level of energy.

Various embodiments of the present subject matter modulate baroreflexstimulation using a pre-programmed template intended to match thecircadian rhythm for a number of subjects. Various embodiments of thepresent subject matter generate a template customized to match asubject.

FIG. 22 illustrates a method for modulating baroreceptor stimulationbased on circadian rhythm, according to various embodiments of thepresent subject matter, using a customized circadian rhythm template.The illustrated method 2222 senses and records parameters related tohypertension at 2223. Examples of such parameters include heart rate andmean arterial pressure. At 2224, a circadian rhythm template isgenerated based on these recorded parameters. At 2225, the baroreflexstimulation is modulated using the circadian rhythm template generatedin 2224.

Modulation of Baroreflex Stimulation to Provide Desired Cardiac Output

An aspect of the present subject matter relates to an implantablemedical device that provides NS therapy to lower systemic blood pressureby stimulating the baroreflex, and further provides cardiac pacingtherapy using a cardiac pacing lead for rate control. Baroreflexstimulation and cardiac pacing occurs in tandem, allowing blood pressureto be lowered without sacrificing cardiac output.

According to various embodiments, a baroreflex stimulator communicateswith a separate implantable CRM device, and uses the existing pacinglead. In various embodiments, baroreflex stimulation occurs throughbaroreceptors in the pulmonary artery, carotid sinus, or aortic archwith an electrode placed in or adjacent to the vessel wall. In variousembodiments, afferent nerves such as the aortic nerve, carotid sinusnerve, or vagus nerve are stimulated directly with a cuff electrode.

Baroreflex stimulation quickly results in vasodilation, and decreasessystemic blood pressure. To compensate for the concurrent decrease incardiac output, the pacing rate is increased during baroreflexstimulation. The present subject matter allows blood pressure to begradually lowered through baroreflex stimulation while avoiding the dropin cardiac output that otherwise accompanies such stimulation bycombining baroreflex stimulation with cardiac pacing, allowing animplantable device to maintain cardiac output during blood pressurecontrol.

FIG. 23A-B illustrate methods for modulating baroreceptor stimulationbased on a cardiac output parameter, according to various embodiments ofthe present subject matter. FIG. 23A illustrates one embodiment formodulating baroreceptor stimulation based on a cardiac output parameter.In the illustrated process 2326A, it is determined whether baroreflexstimulation is being applied at 2327. If baroreflex stimulation is notbeing applied, the present subject matter implements the appropriatepacing therapy, if any, at 2328 with the appropriate pacing rate. Ifbaroreflex stimulation is not being applied, the present subject matterimplements a pacing therapy at 2329 with a higher pacing rate tomaintain cardiac output.

FIG. 23B illustrates one embodiment for modulating baroreceptorstimulation based on a cardiac output parameter. In the illustratedprocess 2326B, baroreflex stimulation is applied at 2330, and it isdetermined whether the cardiac output is adequate at 2331. Upondetermining that the cardiac output is not adequate, the pacing rate isincreased at 2332 to maintain adequate cardiac output.

According to various embodiments, an existing pacing rate is increasedby a predetermined factor during baroreflex stimulation to maintaincardiac output. In various embodiments, a pacing rate is initiatedduring baroreflex stimulation to maintain cardiac output. Modulatingbaroreflex stimulation to provide desired cardiac output can beimplemented with atrial and ventricular rate control, AV delay control,resynchronization, and multisite stimulation. Alternatively, the strokevolume may be monitored by right ventricular impedance using electrodeswithin the right ventricular cavity or by left ventricular impedanceusing electrodes within or spanning the left ventricular cavity, and thepacing rate may be increased using application of neural stimulation tomaintain a fixed cardiac output.

Modulation of Baroreflex Stimulation to Remodel Stiffening Process

Aspects of the present subject matter involve a method for baroreflexstimulation, used by an implantable NS device, to lower systemic bloodpressure in patients with refractory hypertension. A baroreflexstimulation algorithm gradually increases baroreflex stimulation toslowly adjust blood pressure towards a programmable target. Thisalgorithm prevents the central nervous system from adapting to aconstant increased level of baroreflex stimulation, which ordinarilyattenuates the pressure-lowering effect. In addition, the gradual natureof the blood pressure change allows the patient to better tolerate thetherapy, without abrupt changes in systemic blood pressure and cardiacoutput.

The present subject matter provides a specific algorithm or processdesigned to prevent central nervous system adaptation to increasedbaroreflex stimulation, to slowly decrease blood pressure levels withtime to enable for the reversion of the arterial stiffening processtriggered by the previous hypertensive state present in the patient, andto prevent cardiac output decreases during baroreceptor stimulation. Itis expected that, with time, the arterial system reverse remodels thestiffening process that was started by the previously presenthypertension. The slow and progressive lowering of the mean/median bloodpressure enables the slow reversion of this stiffening process throughthe reverse remodeling. Blood pressure is reduced without compromisingcardiac output in the process, thus avoiding undesired patient symptoms.

In various embodiments, the device stimulates baroreceptors in thepulmonary artery, carotid sinus, or aortic arch with an electrode placedin or adjacent to the vessel wall. In various embodiments afferentnerves such as the aortic nerve, carotid sinus nerve, or vagus nerve arestimulated directly with a cuff electrode. The stimulated baroreflexquickly results in vasodilation, and a decrease in systemic bloodpressure. However, rather than stimulating the baroreflex at a constant,elevated level, the device of the present subject matter initiallystimulates at a slightly increased level, and then gradually increasesthe stimulation over a period of weeks or months, for example. The rateof change is determined by the device based on current and targetarterial pressure. In various embodiments, the system determines therate of change based on direct or indirect measurements of cardiacoutput, to ensure that the decrease in pressure is not occurring at theexpense of a decreased cardiac output. In various embodiments, the rateof baroreflex stimulation is not constant but has a white noise typedistribution to more closely mimic the nerve traffic distribution. Bymimicking the nerve traffic distribution, it is expected that thebaroreflex is more responsive to the stimulation, thus lowering thethreshold for stimulating the baroreflex.

FIG. 24 illustrates a method for modulating baroreceptor stimulation toreverse remodel stiffening, according to various embodiments of thepresent subject matter. A baroreflex event trigger occurs at 2433. Thistrigger includes any event which initiates baroreflex stimulation,including the activation of an AHT device. At 2434, an algorithm isimplemented to increase baroreflex stimulation by a predetermined rateof change to gradually lower the blood pressure to a target pressure inorder to reverse remodel the stiffening process. At 2435, it isdetermined whether to continue with the baroreflex stimulationalgorithm. The algorithm may be discontinued at 2436 based on an eventinterrupt, sensed parameters, and/or reaching the target blood pressure,for example. At 2437, it is determined whether the cardiac output isacceptable. If the cardiac output in not acceptable, at 2438 the rate ofchange for the baroreflex stimulate is modified based on the cardiacoutput.

Baroreflex Stimulation to Treat Myocardial Infarction

Following a myocardial infarction, myocytes in the infarcted region dieand are replaced by scar tissue, which has different mechanical andelastic properties from functional myocardium. Over time, this infarctedarea can thin and expand, causing a redistribution of myocardialstresses over the entire heart. Eventually, this process leads toimpaired mechanical function in the highly stressed regions and heartfailure. The highly stressed regions are referred to as being heavily“loaded” and a reduction in stress is termed “unloading.” A device totreat acute myocardial infarction to prevent or reduce myocardial damageis desirable.

An aspect of the present subject matter relates to an implantable devicethat monitors cardiac electrical activity. Upon detection of amyocardial infarction, the device electrically stimulates thebaroreflex, by stimulating baroreceptors in or adjacent to the vesselwalls and/or by directly stimulating pressure-sensitive nerves.Increased baroreflex stimulation compensates for reduced baroreflexsensitivity, and improves the clinical outcome in patients following amyocardial infarction. An implantable device (for example, a CRM device)monitors cardiac electrical activity. Upon detection of a myocardialinfarction, the device stimulates the baroreflex. Some embodiments ofthe device stimulate baroreceptors in the pulmonary artery, carotidsinus, or aortic arch with an electrode placed in or adjacent to thevessel wall. In various embodiments, afferent nerves such as the aorticnerve are stimulated directly with a cuff electrode, or with a leadintravenously placed near the afferent nerve. Afferent nerves such asthe carotid sinus nerve or vagus nerve are stimulated directly with acuff electrode, or with a lead intravenously placed near the afferentnerve. In various embodiments, a cardiac fat pad is stimulated using anelectrode screwed into the fat pad, or a lead intravenously fed into avessel or chamber proximate to the fat pad.

Baroreflex stimulation quickly results in vasodilation, and a decreasein systemic blood pressure. This compensates for reduced baroreflexsensitivity and reduces myocardial infarction. According to variousembodiments, systemic blood pressure, or a surrogate parameter, aremonitored during baroreflex stimulation to insure that an appropriatelevel of stimulation is delivered. Some aspects and embodiments of thepresent subject matter provides baroreflex stimulation to preventischemic damage following myocardial infarction.

FIGS. 25A-25B illustrate a system and method to detect myocardialinfarction and perform baropacing in response to the detected myocardialinfarction, according to various embodiments of the present subjectmatter. FIG. 25A illustrates a system that includes a myocardialinfarction detector 2539 and a baroreflex or baroreceptor stimulator2540. A myocardial infarction can be detected using anelectrocardiogram, for example. For example, a template can be comparedto the electrocardiogram to determine a myocardial infarction. Anotherexample detects changes in the ST segment elevation to detect myocardialinfarction. In various embodiments, the detector 2539 and stimulator2540 are integrated into a single implantable device such as in an AHTdevice or a CRM device, for example. In various embodiments, thedetector 2539 and stimulator 2540 are implemented in separateimplantable devices that are adapted to communicate with each other.

FIG. 25B illustrates a method to detect myocardial infarction andperform baropacing in response to the detected myocardial infarction,according to various embodiments of the present subject matter. At 2541,it is determined whether a myocardial infarction has occurred. Upondetermining that a myocardial infarction has occurred, the baroreflex isstimulated at 2542. For example, in various embodiments, thebaroreceptors in and around the pulmonary artery are stimulated using alead fed through the right atrium and the pulmonary valve and into thepulmonary artery. Other embodiments stimulate other baroreceptor sitesand pressure sensitive nerves. Some embodiments monitor the systemicblood pressure or a surrogate parameter at 2543, and determines at 2544if the stimulation should be adjusted based on this monitoring. If thestimulation is to be adjusted, the baroreflex stimulation is modulatedat 2545. Examples of modulation include changing the amplitude,frequency, burst frequency and/or waveform of the stimulation.

Neural stimulation, such as baroreflex stimulation, can be used tounload after a myocardial infarction. Various embodiments use an acutemyocardial infraction detection sensor, such as an ischemia sensor,within a feedback control system of an NS device. However, a myocardialinfraction detection sensor is not required. For example, a stimulationlead can be implanted after a myocardial infarction. In variousembodiments, the stimulation lead is implanted through the right atriumand into the pulmonary artery to stimulate baroreceptors in and aroundthe pulmonary artery. Various embodiments implant stimulation cuffs orleads to stimulate afferent nerves, electrode screws or leads tostimulate cardiac fat pads, and leads to stimulate other baroreceptorsas provided elsewhere in this disclosure.

Electrical pre-excitation of a heavily loaded region will reduce loadingon this region. This pre-excitation may significantly reduce cardiacoutput resulting in sympathetic activation and an increase in globalstress, ultimately leading to deleterious remodeling of the heart. Thisprocess may be circumvented by increased neural stimulation to reducethe impact of this reflex. Thus, activation of the parasympatheticnervous system during pre-excitation may prevent the undesirableside-effects of unloading by electrical pre-excitation.

Stimulation Modulation Based on Monitored Cardiovascular Parameter(s)

FIGS. 26A-26B illustrate a system and method to automatically adjust abaroreflex stimulation level to titrate a desired baroreflex therapyover an extended time based on monitored cardiovascular parameter(s),according to various embodiments of the present subject matter.Referring to FIG. 26A, the illustrated baroreflex stimulator 2650includes a pulse generator 2651 to provide baroreceptor stimulation aspart of a baroreceptor therapy, a modulator 2652 to change or modulatethe baroreceptor stimulation, and a cardiovascular parameter monitor2653 to provide parasympathetic response feedback. Various stimulatorembodiments are implantable. The parasympathetic nervous system isgenerally illustrated at 2654. The device 2650 uses appropriateelectrode(s) 2655 to provide desired neural stimulation and sensor(s)2656 to sense a parameter that is quickly affected by the neuralstimulation. Examples of such parameters include heart rate, bloodpressure, and respiration. Other cardiovascular parameter(s) and othersurrogate parameters that have a quick and predictable responseindicative of the overall response of the parasympathetic nervous systemto the neural stimulation. The sensor(s) and electrode(s) can beintegrated on a single lead or can use multiple leads. Additionally,various system embodiments implement the functions illustrated in FIG.26A using an implantable neural stimulator capable of communicating witha distinct or integrated implantable cardiac rhythm management device.

The illustrated monitor 2653 monitors the parameter during a time withstimulation to provide a first feedback signal 2657 indicative of aparameter value corresponding to a time with stimulation and during atime without stimulation to provide a second feedback signal 2658indicative of a parameter value corresponding to a time withoutstimulation. The signals 2657 and 2658 are illustrated as separatelines. These signals 2657 and 2658 can be sent over different signalpaths or over the same signal path. A comparator 2659 receives the firstand second feedback signals 2657 and 2658 and determines a detectedchange in the parameter value based on these signals. Additionally, thecomparator compares the detected change with a desired change, asgenerally represented at 2660. In various embodiments, the desiredchange is a programmable parameter. Various embodiments program thedesired change as a percent change (e.g. 5% to 10% reduction in heartrate from a heart rate during a time without stimulation to a heart rateduring a time with stimulation). Various embodiments the desired changeas a change in quantitative value (e.g. 5 bpm to 10 bpm reduction inheart rate from a heart rate during a time without stimulation to aheart rate during a time with stimulation). A comparison of the detectedchange (based on signals 2657 and 2658) and the desired change (based onvalue 2660) provide a comparison result 2661, which is used toappropriately control the modulator to adjust the applied baroreceptorstimulation. Various modulator embodiments change an amplitude 2662 of astimulation signal used to provide the baroreceptor stimulation. Variousmodulator embodiments change a frequency 2663 of a stimulation signalused to provide the baroreceptor stimulation. Various modulatorembodiments change a burst frequency 2664 of a stimulation signal usedto provide the baroreceptor stimulation. Various modulator embodimentschange a pulse width 2665 of a stimulation signal used to provide thebaroreceptor stimulation. Various modulator embodiments change a dutycycle 2666 of a stimulation signal used to provide the baroreceptorstimulation. Various modulator embodiments change various combinationsof two or more of these stimulation signal characteristics.

The illustrated system is useful in extended therapy applications.Examples of extended therapy applications involve applying stimulationto prevent remodeling of cardiac tissue and to reverse remodel cardiactissue in cardiovascular disease. However, the present subject matterapplies to other extended therapies. Baroreflex stimulation in one ofthese therapies can be applied for a portion (5 to 10 seconds) of eachminute, for example. Over the course of days, weeks, months and years,the efficacy of a given baroreflex stimulation with respect to a desiredresponse of a parasympathetic nervous system can vary for a number ofreasons, such as nerve adaptation, tissue encapsulation, fibrosis,impedance changes, and the like. Additionally, systemic adaptation (i.e.an adaptation that results in attenuation of the heart rate effect inthe absence of changes in the electrode or nerve) can adversely affectthe efficacy of a given baroreflex stimulation over time. Theillustrated system monitors a parameter that has a quick and predictableresponse to an applied neural stimulation, and uses the monitoredparameter to appropriately change the neural stimulation signal toresult in a desired stimulation of the parasympathetic nervous system.

FIG. 26B illustrates a method for operating an implantable medicaldevice, according to various embodiments. At 2670, baroreflexstimulation is intermittently provided for a baroreflex therapy over aperiod of time. The intermittent stimulation can be periodic or at someother intervals. Thus, the stimulation is provided for a time, and isnot provided for a time. At 2671, values for at least one cardiovascularfeedback parameter are compared when the baroreflex stimulation isapplied and when then baroreflex stimulation is not applied to provide adetected feedback change. Various embodiments monitor parameters havinga quick and predictable response to the stimulation such as heart rate,blood pressure, respiration, and the like. At 2672, the detectedfeedback change is compared to a desired feedback change to provide acomparison result. At 2673, the baroreflex stimulation is adjusted basedon the comparison result to control the baroreflex therapy over theperiod of time. In various embodiments, the adjustment is continuouslyperformed when stimulation is applied until a target value for themonitored parameter is reached. In various embodiments, the adjustmentis iteratively performed using subsequent time periods when thestimulation is applied until a target value for the monitored parameteris reached.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the term module is intended to encompass software implementations,hardware implementations, and software and hardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. For example,various embodiments combine two or more of the illustrated processes.Two or more sensed parameters can be combined into a composite parameterused to provide a desired neural stimulation (NS) or anti-hypertension(AHT) therapy. In various embodiments, the methods provided above areimplemented as a computer data signal embodied in a carrier wave orpropagated signal, that represents a sequence of instructions which,when executed by a processor cause the processor to perform therespective method. In various embodiments, methods provided above areimplemented as a set of instructions contained on a computer-accessiblemedium capable of directing a processor to perform the respectivemethod. In various embodiments, the medium is a magnetic medium, anelectronic medium, or an optical medium.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement which is calculated to achieve the same purpose maybe substituted for the specific embodiment shown. This application isintended to cover adaptations or variations of the present subjectmatter. It is to be understood that the above description is intended tobe illustrative, and not restrictive. Combinations of the aboveembodiments as well as combinations of portions of the above embodimentsin other embodiments will be apparent to those of skill in the art uponreviewing the above description. The scope of the present subject mattershould be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled.

1. A system for providing baroreflex stimulation, comprising: a heartrate monitor to sense a heart rate and provide a signal indicative ofthe heart rate; and a baroreflex stimulator, including: a pulsegenerator to chronically deliver an efficacious intermittent baroreflexstimulation, wherein the pulse generator is programmed to generate astimulation signal in a recurring succession of stimulation cycles toprovide the efficacious intermittent baroreflex stimulation, wherein thestimulation signal is generated for a portion of each stimulation cycleand is not generated for another portion of each stimulation cycle; andwherein the efficacious intermittent baroreflex stimulation isassociated with a programmed target heart rate change between a firstheart rate during the portion of each stimulation cycle when thestimulation signal is generated and a second heart rate during the otherportion of each stimulation cycle when the stimulation signal is notgenerated; and a modulator to adjust the stimulation signal based on thesignal indicative of the heart rate such that the stimulation signalresults in the target heart rate change between the first heart rate andthe second heart rate to maintain efficacy of the efficaciousintermittent baroreflex stimulation.
 2. The system of claim 1, whereinthe target heart rate change includes a percent change.
 3. The system ofclaim 1, wherein the target heart rate change includes a quantitativechange.
 4. The system of claim 1, wherein the modulator is adapted toadjust an amplitude of the stimulation signal.
 5. The system of claim 1,wherein the modulator is adapted to adjust a frequency of thestimulation signal.
 6. The system of claim 1, wherein the modulator isadapted to adjust a burst frequency of the stimulation signal.
 7. Thesystem of claim 1, wherein the modulator is adapted to adjust a pulsewidth of the stimulation signal.
 8. The system of claim 1, wherein themodulator is adapted to adjust any combination of at least twostimulation signal attributes from a group of stimulation signalattributes consisting of: an amplitude, a frequency, a burst frequency,and a pulse width.
 9. The system of claim 1, wherein the chronic,efficacious intermittent baroreflex stimulation includes efficaciousstimulation to prevent remodeling of cardiac tissue or efficaciousstimulation to reverse remodel cardiac tissue.
 10. The system of claim1, further comprising an implantable neural stimulator (NS) device andan implantable cardiac stimulator, wherein the implantable NS deviceincludes the baroreflex stimulator and the implantable cardiacstimulator includes the heart rate monitor.
 11. The system of claim 1,further comprising an implantable neural stimulator (NS) device, whereinimplantable NS device includes the baroreflex stimulator and the heartrate monitor.
 12. The system of claim 1, wherein the portion of eachstimulation cycle when stimulation is generated occurs at a periodicinterval.
 13. The system of claim 1, wherein the portion of eachstimulation cycle when stimulation is generated occurs at an intervalother than a periodic interval.
 14. A system for providing baroreflexstimulation, comprising: a baroreflex stimulator, including: a pulsegenerator to chronically deliver an efficacious intermittent baroreflexstimulation, the pulse generator to generate a stimulation signal in arecurring succession of stimulation cycles to provide the intermittentbaroreflex stimulation where each stimulation cycle has a “stimulationon” portion and a “stimulation off” portion, wherein the efficaciousintermittent baroreflex stimulation is associated with a target changebetween a first value for a cardiovascular parameter during the“stimulation on” portion of each cycle and a second value for thecardiovascular parameter during the “stimulation off” portion of eachcycle; and a modulator to adjust the stimulation signal; acardiovascular parameter monitor to monitor the cardiovascular parameterand provide a first signal indicative of the cardiovascular parameterduring the “stimulation on” portion and a second signal indicative ofthe cardiovascular parameter during the “stimulation off” portion; and acomparator to provide a detected change for the cardiovascular parameterbased on the first and second signals, and to provide a therapy controlsignal based on the target change for the cardiovascular parameter andthe detected change to maintain efficacy of the efficacious intermittentbaroreflex stimulation.
 15. The system of claim 14, wherein themodulator is adapted to adjust at least one stimulation signal attributefrom a group of stimulation signal attributes consisting of: anamplitude, a frequency, a burst frequency, and a pulse width.
 16. Thesystem of claim 14, wherein the cardiovascular parameter monitor isadapted to monitor a heart rate.
 17. The system of claim 14, wherein thecardiovascular parameter monitor is adapted to monitor a blood pressure.18. The system of claim 14, wherein the cardiovascular parameter monitoris adapted to monitor a respiration rate.
 19. The system of claim 14,wherein the target change includes a percent change.
 20. The system ofclaim 14, wherein the target change includes a quantitative change. 21.The system of claim 14, wherein the “stimulation on” portion of eachcycle occurs at a periodic interval.
 22. The system of claim 14, whereinthe “stimulation on” portion of each cycle occurs at an interval otherthan a periodic interval.
 23. A baroreflex stimulator, comprising: meansfor chronically providing efficacious intermittent baroreflexstimulation, wherein the means for chronically providing efficaciousintermittent baroreflex stimulation includes means for generating astimulation signal in a recurring succession of stimulation cycles whereeach stimulation cycle has a “stimulation on” portion and a “stimulationoff” portion, wherein an efficacy of the efficacious intermittentbaroreflex stimulation is associated with a target feedback change for acardiovascular feedback parameter; means for comparing a first value forthe cardiovascular feedback parameter for “stimulation on” portions ofthe cycles to a second value for “stimulation off” portions of thecycles to provide a detected feedback change; means for comparing thedetected feedback change to the target feedback change to provide acomparison result; and means for adjusting the efficacious intermittentbaroreflex stimulation based on the comparison result to maintain theefficacy of the efficacious intermittent baroreflex stimulation.
 24. Thebaroreflex stimulator of claim 23, wherein the efficacious intermittentbaroreflex stimulation includes efficacious stimulation to preventremodeling of cardiac tissue or efficacious stimulation to reverseremodel of cardiac tissue.
 25. The baroreflex stimulator of claim 23,wherein the means for comparing includes means for comparing a firstheart rate value for “stimulation on” portions to a second heart ratevalue for “stimulation off” portions.
 26. The baroreflex stimulator ofclaim 23, further comprising means for programming the target feedbackchange.
 27. The baroreflex stimulator of claim 23, wherein the means forproviding efficacious intermittent baroreflex stimulation includes meansfor stimulating an afferent nerve using a cuff electrode.
 28. Thebaroreflex stimulator of claim 23, wherein the means for providingefficacious intermittent baroreflex stimulation includes means fortransvascularly stimulating an afferent nerve using anintravascularly-fed electrode.
 29. The baroreflex stimulator of claim23, wherein the means for providing efficacious intermittent baroreflexstimulation includes means for stimulating a cardiac fat pad using anelectrode positioned in the cardiac fat pad.
 30. The baroreflexstimulator of claim 23, wherein the means for providing efficaciousintermittent baroreflex stimulation includes means for transvascularlystimulating a cardiac fat pad using an intravascularly-fed electrode.31. A method, comprising: chronically providing efficacious intermittentbaroreflex stimulation; wherein chronically providing the efficaciousintermittent baroreflex stimulation includes generating a stimulationsignal in a recurring succession of stimulation cycles, and an efficacyof the chronic intermittent baroreflex stimulation is associated with atarget feedback change for a cardiovascular feedback parameter; whereingenerating the stimulation signal includes generating the stimulationsignal for a portion of each stimulation cycle and not generating thestimulation signal for another portion of each stimulation cycle;comparing a first value for the cardiovascular feedback parametercorresponding to the portion of each cycle when the stimulation cycle isgenerated and a second value corresponding to the other portion of eachcycle when the stimulation cycle is not generated to provide a detectedfeedback change; comparing the detected feedback change to the targetfeedback change to provide a comparison result; and adjusting thebaroreflex stimulation based on the comparison result to maintain theefficacy of the efficacious intermittent baroreflex stimulation.
 32. Themethod of claim 31, further comprising programming the target feedbackchange for use in comparing the detected feedback change to the targetfeedback change.
 33. The method of claim 32, wherein programming thetarget feedback change includes programming a percent change.
 34. Themethod of claim 32, wherein programming the target feedback changeincludes programming a quantitative value change.
 35. The method ofclaim 31, wherein providing efficacious intermittent baroreflexstimulation includes providing efficacious stimulation to preventremodeling of cardiac tissue or providing efficacious stimulation toreverse remodel cardiac tissue.
 36. The method of claim 31, wherein theat least one cardiovascular feedback parameter includes heart rate. 37.The method of claim 31, wherein the at least one cardiovascular feedbackparameter includes blood pressure.
 38. The method of claim 31, whereinthe at least one cardiovascular feedback parameter includes respiration.39. The method of claim 31, wherein adjusting the baroreflex stimulationincludes adjusting an amplitude of a baroreflex signal used to providethe baroreflex stimulation.
 40. The method of claim 31, whereinadjusting the baroreflex stimulation includes adjusting a frequency of abaroreflex signal used to provide the baroreflex stimulation.
 41. Themethod of claim 31, wherein adjusting the baroreflex stimulationincludes adjusting a burst frequency of a baroreflex signal used toprovide the baroreflex stimulation.
 42. The method of claim 31, whereinadjusting the baroreflex stimulation includes adjusting a pulse width ofa baroreflex signal used to provide the baroreflex stimulation.
 43. Themethod of claim 31, wherein generating the stimulation signal for aportion of each stimulation cycle includes initiating the portion ofeach stimulation cycle at a periodic interval.
 44. The method of claim31, wherein generating the stimulation signal for a portion of eachstimulation cycle includes initiating the portion of each stimulationcycle at an interval other than a periodic interval.